Overall - Project Summary/Abstract: The contamination of water and aquifer sediments with arsenic (As) is associated with major public health and environmental mitigation issues in the United States. At present, 823 of 1739 U.S. Superfund sites list As as a major contaminant; in addition millions of U.S. residents are unduly exposed due to naturally occurring As in their household well water. This proposal includes two biomedical and two geoscience projects that seek to address critically important issues that collectively aim to reduce As exposure and toxicity in exposed human populations in the U.S. and in Bangladesh, where much information can be learned that will benefit residents of the U.S. and elsewhere. The proposal builds on the strengths of our existing longitudinal cohort study of 35,000 adults in Bangladesh by examining dose-response relationships between As exposure (in the low-mid range) from contaminated food and water with incident cases (and sub-types) of cardiovascular disease (CVD) and non-malignant lung disease, as well as diabetes mellitus (DM). In addition, we will combine and meta-analyze data from Bangladesh, Taiwan, China (Inner Mongolia) and the U.S. (AZ, CO, ND, OK, SD) to refine the dose-response relationships between As exposure and CVD. We build off our previous observations that: a) As exposure is associated with deficits in child intelligence; and b) that folate, a B vitamin, facilitates As metabolism and elimination in adults. We propose to conduct a randomized clinical trial in 8-10 year old children in Bangladesh to test the hypothesis that folate+B12 supplementation can: a) lower blood As; and b) improve cognitive abilities in children. Building on our previous geoscience research which indicates that in situ magnetite formation forms a diffuse barrier capable of long-term As retention, we propose to conduct laboratory and field research to optimize and implement this new approach at a U.S. Geological Survey research site on Cape Cod, MA and a Superfund site in Raleigh, NC. In Bangladesh, we will quantify the geographic and socio-political barriers to reducing As exposure by analyzing the vast data sets accumulated in our main study area and we will conduct a randomized controlled trial comparing ways to overcome some of them. In parallel, we will continue to examine the potential vulnerability to human perturbations of shallow and deep aquifers that are low in As. These low As aquifers are crucial for reducing exposure to our study population and the country at large. In the U.S., we will build on our proven success of partnering with state and local governments to reduce As exposure in communities that rely on As-contaminated household wells in ME, NJ and MN. We will also continue to facilitate effective communication among our SRP scientists, stakeholders and government partners via five specific strategies. Finally, we will continue to train the next generation of scientists with disciplinary and inter-disciplinary skills that will enable them to improve the health of those who reside in environments that might expose them to As and other contaminants in soil, water and food.